Download Cryptogenic Stroke

PFO closures: Is there a need?
Lowell Satler, MD
Washington Hospital Center
DISCLOSURES
Lowell F. Satler, MD
Grants/Contracted Research
– Medtronic CardioVascular, Inc., Edwards
Lifesciences LLC, Abbott Vascular
Speakers Bureau
-Daiichi-Sankyo, Inc.
-Eli Lilly and Company
Patent Foramen Ovale (PFO)
• Persistent flap-like
opening: atrial septum
primum and secundum
• In utero, physiologic rightto-left shunting
• After birth, increased left
atrial blood flow and
pressure closes flap
• Anatomical closure follows
3
Atrial Septal Anatomy
SVC
Foramen Ovale
LA
Septum Primum
Superior & Inferior Limbic
Ridges
Fossa Ovalis
Coronary Sinus
Eustachian
Valve
IVC
RV
Presumed mechanism of Stroke with PFO
Pressure in RA > Pressure
in LA:
• Early systole
• Valsalva
• Coughing
• Pulmonary hypertension
• COPD
• Pregnancy
• Asthmatics
• Wind instruments
• Decompression sickness
(diving)
• High altitude flying
• Obstructive sleep
patterns
PRA
PLA
RA
LA
Role of PFO in Clinical Disease
• Cardioembolic stroke
• Cryptogenic stroke
• Brain abscess
• Platypnea-orthodeoxia
• Migraine with aura
• Decompression illness
ischemia/stroke
• Wind instrument
Classification & Etiology of Strokes
Ischemic (approximately 88%)
• Thrombotic
• Embolic
• Cryptogenic (up to 40%)
Hemorrhagic (approximately 12%)
• Subarachnoid
• Parenchymal
Broderick J, et al, The Greater Cincinnati/Northern Kentucky Stroke Study: preliminary first-ever and total incidence rates of stroke among
blacks. Stroke, 1998 Feb; 29(2): 415-21.
Rosamond W, et al, American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics-2008 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee, Circulation, 2008 Jan;
29;117(4): e25-146. Epub 2007 Dec 17
Meissner I, et al, Prevalence of potential risk factors for stroke assessed by transesophageal echocardiography and carotid ultrasonography:
the SPARC study, Stroke Prevention: Assessment of Risk in a Community, Mayo Clin Proc. 1999 Sep; 74(9): 862-9.
Sources of Cardiogenic Emboli
Left Atrium
• Atrial fibrillation
Paradoxical Emboli
• Patent foramen
ovale
• Atrial septal
defect
• Myxoma
• Atrial septal aneurysm
Aortic Valve
• Calcific stenosis
• Infective
endocarditis
• Prosthetic valve
Mitral Valve
• Infective endocarditis
• Non-bacterial endocarditis
• Myxomatous valvulopathy
• Prosthetic valves
• Vegetations due to
prothrombotic states
Left Ventricle
• Ischemic
dyskinesis
• Cardiomyopathy
• Thrombi due to
prothrombotic
states
Cryptogenic Stroke
•700,000 strokes/yr in US
•80-85% ischemic
•30-40% of strokes remain defined as cryptogenic
•40-60% frequency of PFO among cryptogenic strokes
•~100,000 strokes/yr with PFO as only identified potential
etiology
Kim D, Saver JL. Reviews in Neurological Diseases
2005;2(1):1-7
Implication of PFO in Cryptogenic Stroke
Prevalence of PFO in “Normal” Population: 10-25%
Lechat, et al - NEJM 5/88
Webster, et al - Lancet 1988
Mayo Autopsy Study
Prevalence in Stroke Population <60 y.o.: 40-50%
Ranous, Mas, et al - STROKE 1/93
Webster, et al - Lancet 1988
Lausanne Study - Neurology 5/96
Lechat, et al - NEJM 5/88
Case 1
• 55 year old man
• Hx: AAA, smoker, HTN, chol, achilles repair 1 week
PTA
• Acute left motor deficits, dysarthria over 2 hours
• Outside ER: CT, labs, EKG, US, ECHO, leg doppler
• Outside Diagnosis: TIA
Case 1
Work-up:
• MRI: acute right parietal infarct
• TCD Bubble: shunting
• TEE: moderate PFO with ASA
• Coags: negative
• Homocysteine: 20
What is the ideal treatment?
Case 2
• 50 year old medical school professor
• No PMH or vascular risk factors
• Event:
• During 9 hour air travel, reads book, does not get up.
• After flight, enters terminal walking to customs. Has
vigorous sneezing.
• Within minutes becomes confused and staggers to floor,
but recovers in minutes.
• Hospitalized.
Case 2
MRI: acute right MCA territory infarcts suggesting embolus
TEE: Demonstrates PFO
Case 2
Work-up:
• normal CTA head and neck, routine ECHO, BP,
coagulation labs, extremity dopplers
• ECHO with bubble reveals large PFO with shunting at
valsalva
Diagnosis:
• Presumed extremity/pelvic vein clot related to stasis
(prolonged sit during air travel) with paradoxical embolus
after mobilizing clot (walking) and powerful valsalva
(sneeze)
What is the ideal treatment?
PFO: AAN Practice Guidelines 2004
• There is insufficient evidence of superiority of aspirin
or warfarin
• Risks of minor bleeding appear greater with warfarin
• There is insufficient evidence to evaluate efficacy of
surgical or endovascular closure
Messe, et al, Neurology 2004; 62, 1042-1050
AHA-ASA 2006 Secondary Prevention Guidelines
• Insufficient data exist to make a recommendation
about PFO closure in patients with a first stroke and a
PFO.
To Close or Not to Close
The RESPECT PFO Clinical Trial
is designed to help answer this
question.
Randomized Evaluation of
Recurrent Stroke Comparing
PFO Closure to Established
Current Standard of Care
Treatment
IDE #G990318
Clinical Trial Design
• The RESPECT PFO Clinical Trial is a randomized evaluation
comparing device closure plus medical therapy to current
medical therapy standard of care
• Maximum 900 patients (450 per arm)
• Maximum 75 participating institutions across the U.S.
Clinical Trial Design Overview
Subjects:
• Recent cryptogenic stroke
• 18-60 years of age
Treatment:
• PFO device closure versus medical therapy
Endpoints:
• Stroke or Death
Randomization Groups
• Device closure plus medical therapy will include the
AMPLATZER PFO Occluder and clopidogrel for one
month and aspirin for six months
• Medical therapy current standard of care will include one
of the four following treatments:
• Aspirin alone
• Clopidogrel alone
dipyridamole
• Warfarin alone
• Aspirin in combination with
Study Objective
To investigate whether percutaneous PFO closure is
superior to current standard of care medical treatment in
the prevention of recurrent embolic stroke.
Selection Criteria
Patients with PFO who have had a cryptogenic stroke due
to presumed paradoxical embolism within the last 270
days.
Stroke - Definition
Acute focal neurological deficit presumed to be due to focal
ischemia, and either:
1) Symptoms persisting 24 hours or greater, or
2) Symptoms persisting less than 24 hours but
associated with MR or CT findings of a new,
neuroanatomically relevant, cerebral infarct
Study Endpoints
Primary Endpoint:
• Recurrence of a Nonfatal Stroke, Post-randomization
Death, or Fatal Ischemic Stroke
Study Endpoints
Secondary Endpoints:
• Complete closure of the defect demonstrated by TEE
and bubble study at 6-month follow-up (device group)
• Absence of recurrent symptomatic cryptogenic nonfatal
stroke or cardiovascular death
• Absence of TIA
Required Baseline Testing
Medical History:
Exclusion Criteria
• Age <18 years or >60 years
• Active endocarditis or other untreated infections
• Acute or recent (within 6 months) MI or unstable angina
• Organ failure (kidney, liver or lung)
• Uncontrolled hypertension (>160/90mmHg)
• Uncontrolled diabetes mellitus
Required Baseline Testing
Coagulation:
• A hypercoagulation panel sent to a core lab
Exclusion Criteria
• Patients who test positive for Anticardiolipin Ab of the
IgG or IgM, Lupus Anticoagulant, B2-glycoprotein-1
antibodies or persistently elevated plasma
Homocysteine despite medical therapy.
Required Baseline Testing
TEE with Bubble Study:
Exclusion Criteria
• Intracardiac thrombus or tumor
• Left ventricular aneurysm or akinesis
• Mitral valve stenosis or severe mitral
regurgitation irrespective of etiology
• Aortic valve stenosis (gradient >40 mmHg) or
severe aortic valve regurgitation
• Mitral or aortic valve vegetation or prosthesis
Required Baseline Testing
TEE with Bubble Study:
Exclusion Criteria Continued
• Aortic arch plaques protruding >4mm into the lumen
• Left ventricular dilated cardiomyopathy with LVEF<
35%
• Subjects with other source of right to left shunts
identified at baseline, including an ASD and/or
fenestrated septum
• Anatomy in which the AMPLATZER PFO Occluder
would interfere with intracardiac or intravascular
structures such as valves or pulmonary veins
Required Baseline Testing
ECG or Holter
Exclusion Criteria:
• Atrial fibrillation/atrial flutter (chronic or intermittent)
Pregnancy Test
Exclusion Criteria:
• Pregnant or desire to become pregnant within the next
year
33
Device Description
• Self Expandable
• Nitinol wire 0.005 0.006”
• Polyester Patch
• Short connecting waist
• Sizes: 18, 25 and
35mm
Endothelialization – Six Weeks Post-implant
35
Follow-up Schedule
Pre-discharge (device only):
• One month, six months, 12 months, 18 months, and
24 months, and annually until study end
Six-month Visit:
• TEE with bubble study required for device subjects
36
To Close or Not to Close: Summary
• Closure of Patent Foramen Ovale (PFO) for cryptogenic
stroke is controversial
• Medical therapy carries low risk of complications
• Device closure may carry a low peri-procedural risk
compared to surgery
• No randomized data published
• Clinical trials are ongoing to evaluate device based
closure and gain FDA approval for this indication
Management of Patients with PFO After
Cerebral Events
Therapy
Recommended by
PFO closure in patients with recurrent
cryptogenic stroke despite medical
therapy
AAN
Antiplatelet therapy
Warfarin in the presence of deep vein
thrombosis
Warfarin in the presence of
coagulation abnormalities
Warfarin rather than antiplatelet agents
in the presence of ASA
AAN, AHA/ASA, ESO, ACCP
AHA/ASA, ESO, ACCP
AHA/ASA
AAN
ACCP= American College of Chest Physicians; AAN=American Association of Neurology; AHA/ASA=American
Heart Association/American Stroke Association; and ESO, European Stroke Organization.
Randomized Controlled Trials on PFO Closure
to Prevent Recurrent Paradoxical Ischemic
Events
PC*
Closure-I
RESPECT
CLOSE
Gore
REDUCE
Device Used
Starting
Year
Target
Enrollment, n
Final Status
Projected
Publication
Amplatzer PFO
occluder
2000
450
Finished
enrollment at
420
2011
STARFlex
occluder
2003
1600
Finished
enrollment
2011
Amplatzer PFO
occluder
2004
900 (endpoint
driven)
Enrolling
2013
Free choice
2007
900
Enrolling
2014
HELEX
occluder
2008
664
Enrolling
2016
Randomized Controlled Trials for PFO Closure
in Migraine Headache Patients
Acronym
Place
Sham
Procedure
Device
Status
UK
+
STARFlex
Reported
Global
-
Amplatzer
Recruiting
PREMIUM
US
+
Amplatzer
Recruiting
MIST II
US
+
BioSTAR*
Abandoned
ESCAPE
US
+
Premere†
Abandoned
Global
+
FlatStent‡
Planned
MIST
PRIMA
?
Top Ten Things to Know
Percutaneous Device Closure of Patent
Foramen Ovale for Secondary Stroke Prevention
 Stroke is the third leading cause of death among adults in
the United States and a major contributor to long-term
functional impairment and disability.
 The majority of strokes are ischemic; of these, about 2540% do not have identifiable cause after thorough
evaluation and are designated as cryptogenic (CS).
 A patent foramen ovale (PFO) is a remnant of the fetal
circulation and has been identified at autopsy in 27% of
patients with normal hearts.
Top Ten Things to Know
Percutaneous Device Closure of Patent
Foramen Ovale for Secondary Stroke Prevention
 Many observational studies suggest a strong association
between PFO and CS. But a causal relationship has not
been convincingly established for most affected patients.
 The optimal therapy for prevention of recurrent stroke or
transient ischemic attack in patients with CS and PFO has
not been defined.
 Estimates of annual rates of recurrent stroke among
patients with PFO range from 1.5 – 12% and depend on
the characteristics of the population studied, including
age.
Top Ten Things to Know
Percutaneious Device Closure of Patent
Foramen Ovale for Secondary Stroke Prevention: 2010
 No device for PFO closure after cryptogenic stroke has been
approved by the FDA.
 Randomized controlled trials offer the best means for
assessing the safety and efficacy of percutaneous device
closure relative to anti-thrombotic meds.
 Enrollment in ongoing clinical trials has lagged considerably
despite frequent calls for participation from the FDA and major
professional societies.
 All cardiovascular clinicians should consider referral of patients
with cryptogenic stroke and PFO an ongoing studies.